The present invention relates to pharmaceutical compositions comprising dapagliflozin and cyclodextrin, preferably as inclusion complexes, further preferably to molecularly dispersed dapagliflozin, comprising cyclodextrin, preferably (2-hydroxy)propyl-b-cyclodextrin or γ-cyclodextrin, and dapagliflozin. The invention further relates to a process for producing said pharmaceutical compositions and to dosage forms comprising said pharmaceutical compositions.
“Dapagliflozin” is reported to be the INN name of the C-aryl glucoside compound (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol and can be characterized by the following chemical formula:

Dapagliflozin is reported to inhibit subtype 2 of the sodium-glucose transport proteins (SGLT2), which is responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter causes blood glucose to be eliminated through the urine. In particular, dapagliflozin is indicated for the treatment for type 1 and type 2 diabetes, in particular, type 2 diabetes.
Dapagliflozin and its synthesis are described in EP 1 506 211 B1. WO 2004/063209 A2 is directed to a process for preparing dapagliflozin and intermediates.
In the art, several dapagliflozin formulations are known. EP 1 506 211 B1 mentions combinations of dapagliflozin with an antidiabetic agent other than SGLT2 inhibitor, an agent for treating the complications of diabetes, an anti-obesity agent, an anti-hypertensive agent, an anti-platelet agent, an anti-atherosclerotic agent, and/or a lipid-lowering agent.
WO 2008/116179 A1 seems to disclose an immediate release formulation comprising dapagliflozin and propylene glycol hydrate.
WO 2008/116195 A2 refers to the use of an SLGT2 inhibitor in the treatment of obesity, wherein the amount of said SGLT2 inhibitor is below the effective amount for treating diabetes.
The micronization of dapagliflozin, however, involves some disadvantages. Firstly, the micronization in the active ingredient results in an undesired low flowability. Furthermore, the micronized active ingredient is more difficult to be compressed and occasionally irregular distribution of the active ingredient can occur within the pharmaceutical formulation to be compressed. Caused by the large extension of the surface during micronization, the tendency of the active ingredient to oxidate increases. Moreover, dapagliflozin when provided in crystalline form is hygroscopic. Thus, it tends to attract water molecules from the surrounding environment through absorption, which leads to diffluence of the active substance, thereby impairing processing abilities and storage stability.
Hence, it was an object of the present invention to overcome the drawbacks of the above-mentioned formulations.
In particular, dapagliflozin should be provided in a form having superior solubility and processing abilities. Preferably, dapagliflozin should be provided in a form, which is highly soluble. In addition, dapagliflozin should be provided in a form, which allows oral application independently from meals. The increase in solubility and permeability should particularly be achieved without a micronization step and preferably without the use of excipients or co-solvents. Moreover, dapagliflozin should be provided in a non-hygroscopic form.
Furthermore, it was an object of the invention to provide dapagliflozin in a form having superior storage properties. Preferably, storage stability for 12 months at 40° C. and 75% humidity should be achieved. After storage under said conditions, impurities should be less than 2 wt.-%, more preferably less than 1 wt.-%.
Particularly, the above-mentioned objects should be solved simultaneously, that means, dapagliflozin should be provided in a non-hygroscopic form having high solubility, high permeability and showing high storage stability.